Small airways have been implicated by physiological evidence as the major anatomic site of obstruction in human chronic obstructive lung disease (COPD). However, it is debated as to whether the earliest preclinical stages of the disease are detectable morphologically and physiologically and how they relate to alterations observed later when clinical symptoms are evidenced. The objective of the proposed project is to examine the sequence of changes in the development of morphologic lesions and the progression to disease, corroborating the physiologic evidence. An animal model using chronic nitrogen dioxide (NO2) inhalation which mimics human COPD will be used. Such a model enables study of the entire disease process from injury through disease at the morphological and functional level. Morphometric examination of all tissue components of bronchioles before, during and after injury will make it possible to evaluate whether physiologic evidence of obstruction is due to intrinsic changes of peripheral airways and/or the surrounding supportive peribronchiolar lung parenchyma. Evidence obtained by such a rigorous methodical study of the natural history of small airway disease may supply the necessary data for the development of therapeutic modalities to arrest or reverse the disease process.